Christopher John Montague Meade

Inhibitory effects of the new PAF acether antagonist WEB‐2086 on pharmacologic changes induced by PAF inhalation in human beings

Recent research on asthma mediators has concentrated more and more on platelet‐activating factor (PAF), which is one of the most potent bronchoconstrictors known thus far. Inhalant PAF challenge in healthy volunteers may provide a mean of testing PAF antagonists. The usefulness of the PAF provocation test in measuring the pharmacologic activity of a new PAF antagonist, WEB‐2086, has been examined in 12 healthy volunteers in a double‐blind, placebo‐controlled, within‐subject crossover study. PAF‐induced immediate bronchoconstriction, slight hemodynamic changes, and PAF‐related subjective side effects. Premedication with WEB‐2086 (40 mg) completely prevented any increase in airway resistance after PAF inhalation, as well as development of most of the cardiovascular and side effects induced by PAF. The clear protection against PAF‐induced pharmacologic effects can be explained by the specific PAF‐antagonistic activity of WEB‐2086. The method described in this article may be applied as a useful tool for looking at PAF‐antagonistic activity in healthy volunteers.

Why do asthmatic subjects respond so strongly to inhaled adenosine

Bronchospasm induced by adenosine is blocked by representatives of all the major classes of drugs used in the treatment of asthma. Understanding the mechanism of this bronchospasm may help understand the way these drugs work. Clinical studies have suggested involvement of neural pathways, mast-like cells and mediators such as histamine, serotonin and lipoxygenase products. There is a strong link between responsiveness to adenosine and eosinophilia. In different animal models A1, A2b and A3 adenosine receptor subclasses have all been implicated in inducing bronchospasm. whilst occupation of the A2a receptor generally has no, or the opposite effect. At least two different mechanisms, both involving neural pathways, exist. One, involving the adenosine A1 receptor, functions in mast cell depleted animals; the other requires interaction with a population of mast-like cells activated over A2b or A3 receptors. Not only histamine but also serotonin and lipoxygenase products released from the mast-like cells are potential mediators. In animal models good reactivity to adenosine receptor agonists is generally only found when the animals are first sensitized and exposed to allergen in ways likely to induce an allergic inflammation. An exception is the BDE rat, which reacts to adenosine receptor agonists such as APNEA or NECA even without allergen exposure. This rat strain does however show evidence of spontaneous eosinophilic inflammation in the lung even without immunization. As mast cells both release adenosine and respond to adenosine, adenosine provides a non-specific method of amplifying specific signals resulting from IgE/antigen interaction. This mechanism may not only have a pathological significance in asthma; it may be part of a normal bodily defense response that in asthmatic subjects is inappropriately activated.

Biochemical pharmacology of platelet-activating factor (and PAF antagonists) in relation to clinical and experimental thrombocytopenia.

The object of this review is to relate new developments in the field of platelet-activating factor (PAF) research to the problems of understanding. The cause and perhaps improving the therapy of thrombocytopenia

Safety, tolerability., and pharmacologic activity of multiple doses of the new platelet activating factor antagonist WEB 2086 in human subjects

The safety, tolerability, and pharmacologic activity of WEB 2086, a novel, specific platelet activating factor antagonist, were examined in two double‐blind, placebo‐controlled, within‐subject crossover studies. In each study, WEB 2086 (three times 40 mg/day or three times 100 mg/day) was administered for 7 days to 12 healthy volunteers. Pharmacologic activity of the compound was monitored with ex vivo platelet activating factor–induced platelet aggregation. Multiple administration of WEB 2086 resulted in a continuous, almost complete inhibition of this aggregation. Nevertheless, no clinically significant drug‐related effects on vital and laboratory parameters or obvious drug‐dependent adverse reactions were observed. In conclusion, the performed studies confirmed earlier findings that WEB 2086 was an effective platelet activating factor antagonist in human beings and, furthermore, showed no side effects that would provide objections against further clinical trials with this substance in patients.